Abstract IA003: Immortality and evolution, partners in the cancer crime

Abstract Brain tumor cells acquire an immortal state through a TERT promoter mutation, enabling unrelenting evolution and substantial intratumor heterogeneity (ITH). ITH confounds the effectiveness of therapies and the evaluation of therapeutic response in clinical trials. Glioblastoma is among the most heterogeneous of all solid cancers. However, whether in the context of treatment-naïve tumors at diagnosis or in post-treatment samples from clinical trials, most GBM studies evaluate only a tiny fraction of the tumor. Furthermore, there is no knowledge of where the sample was obtained within the heterogeneous tumor. How can we understand tumor evolution or ITH from one sample unless we assume the remainder of the tumor is homogeneous? For clinical translation, how can we evaluate a precision medicine therapy based on a single sample from a notoriously heterogeneous tumor like GBM? This perspective calls into question our current knowledge of tumor evolution and ITH, and tumor response to therapy. To address this, our multidisciplinary team has developed and deployed a novel, imaging-guided sampling method that collects 10 tissue samples from different regions of the tumor. Each sample is linked to a precise 3D spatial coordinate, allowing projection of genomic results into the original context in the 3D tumor in the patient’s brain. From this approach, we have gained new insights into the cellular organization of whole tumors, tissue microenvironment-related changes to tumor cell gene expression programs and their epigenetic regulation, and the genetic characteristics of the earliest genomic clones that give rise to tumors at diagnosis and recurrence. Finally, we discover new immunotherapeutic targets derived from the dark genome, their cognate T cell receptors, and evidence of their ability to elicit an anti-tumor cell immune response. Citation Format: Nicholas O. Stevers, Radhika Mathur, Benjamin Lerman, Chibo Hong, Shawn Hervey-Jumper, Michael C. Oldham, Joanna J. Phillips, Hideho Okada, Joseph F. Costello. Immortality and evolution, partners in the cancer crime [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr IA003.